ABCC7 p.Tyr1424Phe
| ClinVar: |
c.4272C>T
,
p.Tyr1424=
N
, Benign
|
| CF databases: |
c.4272C>G
,
p.Tyr1424*
(CFTR1)
?
,
|
| Predicted by SNAP2: | A: D (80%), C: D (63%), D: D (91%), E: D (91%), F: N (78%), G: D (91%), H: D (85%), I: D (71%), K: D (91%), L: D (71%), M: D (66%), N: D (85%), P: D (95%), Q: D (85%), R: D (91%), S: D (85%), T: D (85%), V: D (71%), W: D (85%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: N, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: N, |
[switch to compact view]
Comments [show]
None has been submitted yet.
[hide] The carboxyl terminus of the cystic fibrosis trans... J Biol Chem. 2000 Feb 4;275(5):3655-60. Weixel KM, Bradbury NA
The carboxyl terminus of the cystic fibrosis transmembrane conductance regulator binds to AP-2 clathrin adaptors.
J Biol Chem. 2000 Feb 4;275(5):3655-60., 2000-02-04 [PMID:10652362]
Abstract [show]
The cystic fibrosis transmembrane conductance regulator (CFTR) undergoes rapid and efficient endocytosis. Since functionally active CFTR is found in purified clathrin-coated vesicles isolated from both cultured epithelial cells and intact epithelial tissues, we investigated the molecular mechanisms whereby CFTR could enter such endocytic clathrin-coated vesicles. In vivo cross-linking and in vitro pull-down assays show that full-length CFTR binds to the endocytic adaptor complex AP-2. Fusion proteins containing the carboxyl terminus of CFTR (amino acids 1404-1480) were also able to bind AP-2 but did not bind the Golgi-specific adaptor complex AP-1. Substitution of an alanine residue for tyrosine at position 1424 significantly reduced the ability of AP-2 to bind the carboxyl terminus of CFTR; however, mutation to a phenylalanine residue (an amino acid found at position 1424 in dogfish CFTR) did not perturb AP-2 binding. Secondary structure predictions suggest that Tyr(1424) is present in a beta-turn conformation, a conformation disrupted by alanine but not phenylalanine. Together, these data suggest that the carboxyl terminus of CFTR contains a tyrosine-based internalization signal that interacts with the endocytic adaptor complex AP-2 to facilitate efficient entry of CFTR into clathrin-coated vesicles.
Comments [show]
None has been submitted yet.
No. Sentence Comment
99 GST-CT-Y1424F was able to bind AP-2 complexes with as much efficiency as wild-type GST-CT, suggesting that the phenylalanine at position 1424 is capable of participating in the endocytosis signal (Fig. 6B).
X
ABCC7 p.Tyr1424Phe 10652362:99:7
status: NEW101 In contrast, no significant difference was observed between GST-CT-Y1424F and wild-type constructs. A Peptide Derived from the Cytoplasmic Tail of CFTR Inhibits CFTR-AP-2 Binding-To investigate further the role of the carboxyl terminus of CFTR as a docking site for AP-2 adaptors, a peptide representing a cytoplasmic domain sequence of CFTR was tested for its ability to block AP-2 binding to GST-CT constructs. A 19-residue peptide, Y19P (CQQFLVIEEN- KVRQYDSIQ), was synthesized corresponding to amino acids 1410-1428 of CFTR.
X
ABCC7 p.Tyr1424Phe 10652362:101:67
status: NEW154 20 g of Y1424F protein (lane 1), Y1424A (lane 2), wild-type (lane 3), or GST alone (lane 4) were incubated with purified adaptors as described.
X
ABCC7 p.Tyr1424Phe 10652362:154:16
status: NEW169 Such is also the case for CFTR, as a Y1424F mutation resulted in a construct that was unimpaired in its ability to bind AP-2 adaptors.
X
ABCC7 p.Tyr1424Phe 10652362:169:37
status: NEW